TRAIL-DISC formation is androgen-dependent in the human prostatic carcinoma cell line LNCaP
TRAIL-DISC formation is androgen-dependent in the human prostatic carcinoma cell line LNCaP
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DOI：
10.4161/cbt.311
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发表时间：
2002-11-01
影响因子：
3.6
通讯作者：
Cohen, MB
中科院分区：
文献类型：
--
作者：
Rokhlin, OW;Taghiyev, AF;Cohen, MB
我们和其他人先前已经描述了雄激素应答的人前列腺癌细胞系LNCaP对TRAIL具有抗性，并且在LNCaP中TRAIL介导的凋亡是PI 3 K/Akt依赖性的。在这项研究中，我们发现LNCaP在雄激素剥夺后即使在PI 3 K/Akt通路抑制剂渥曼青霉素的存在下也对TRAIL治疗具有抗性。这种抗性是通过雄激素剥夺后未能形成TRAIL-DISC和TRAIL-R1和TRAIL-R2水平降低来确定的;在DHT存在下，TRAIL诱导DISC形成的能力完全恢复。TRAIL和渥曼青霉素一起加速了DISC上半胱天冬酶-8的加工，并明显地加速了半胱天冬酶-8从DISC释放到细胞质中。令人惊讶的是，我们发现渥曼青霉素降低了细胞中TRAIL-R1的总量，但不降低TRAIL-R2的总量以及由TRAIL沉淀的TRAIL-R1的量。我们的数据表明，在LNCaP中，TRAIL-DISC的形成和对TRAIL治疗的敏感性是雄激素依赖性的。
We and others have previously described that the androgen-responsive human prostatic carcinoma cell line LNCaP is resistant to TRAIL and that TRAIL-mediated apoptosis in LNCaP is PI3K/Akt-dependent. In this study, we found that LNCaP remained resistant to treatment with TRAIL after androgen deprivation even in the presence of the PI3K/Akt pathway inhibitor wortmannin. This resistance was determined by failure to form the TRAIL-DISC and by decreased TRAIL-R1 and TRAIL-R2 levels after androgen deprivation; the capacity of TRAIL to induce DISC formation was completely restored in the presence of DHT. TRAIL and wortmannin together accelerated processing of caspase-8 on the DISC and apparently the release of caspase-8 from the DISC into the cytoplasm. Surprisingly, we found that wortmannin decreased the total amount of TRAIL-R1, but not TRAIL-R2, in the cells as well as the amount of TRAIL-R1 precipitated by TRAIL. Our data suggest that TRAIL-DISC formation and sensitivity to TRAIL treatment are androgen-dependent in LNCaP.